Polyomavirus is the genus of the viruses within the family Polyomaviridae. Nine polyomaviruses have been discovered in humans; JCV, BKV, KI virus and WU virus, Merkel cell polyomavirus (MCV), Trichodysplasia sinulosa-associated polyomavirus (TSV), HPyV6, HPyV7, and HPyV9. Among these human polyomaviruses, JCV, BKV, and MCV cause serious complications and diseases. MCV is shown to cause a rare but serious form of skin cancer, merkel cell carcinoma. BKV produces a serious infection of the kidneys of immunosuppressed transplant patients which is a significant basis of graft loss. BKV has a high prevalence in the human population and establishes persistent life long latent infection, typically without clinical symptoms.
Among the human polyomaviruses, JCV is the most abundant polyomavirus which infects more than 80% of the human population during childhood (also typically without clinical symptoms), and establishes a persistent life long latent infection. Reactivation of JCV, which replicates in glial cells in the brain, can cause the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML), which is usually seen in patients with underlying immunocompromised conditions, notably among AIDS patients and those on chronic immunosuppressive regimens.
Little is known about the progression of PML since there is no biomarker for the detection of JCV reactivation and infection in affected individuals. Most PML cases are diagnosed in patients at a late stage of the disease after the onset of the neurological complications. There are no established diagnostic markers applicable to the clinic to predict which patients will develop the disease.
Polyomaviruses such as JCV are non-enveloped, double-stranded DNA viruses. The DNA comprises an early coding region and a late coding region. The early region encodes two oncoproteins called large T antigen (T-Ag) and small t antigen (t-Ag). The late region encodes three capsid proteins, VP1, VP2, and VP3. The detection of polyomavirus DNA and/or anti-polyomavirus antibodies in bodily fluids have been explored as possible methods of diagnosis of polyomavirus reactivation. However, due to the persistent life long infection, such methods have proven somewhat unreliable.
In a subset of polyomaviruses, the late region also encodes a small regulatory protein called agnoprotein. Agnoprotein plays a role in regulation of viral gene expression and replication, and in the modulation of some host cell functions (see, e.g., Khalili et al., J Cell Physiol. 204:1-7, 2005). Agnoprotein is a small, integral membrane protein and is produced late in the infectious cycle (see, e.g, Suzuki et al., PLoS Pathog 6(3):e1000801 doi:10.1371/kpirma;.ppat.100801, 2010). In brain tissue samples from patients with PML, agnoprotein is detected in the perinuclear area and cytoplasmic region of cells in demyelinated lesions, but was not detected in normal areas of the PML brain tissues or in normal brains (Okada et al., Acta Neuropathol 104:130-136, 2002). These data led to the suggestion that such detection of agnoprotein may be useful for diagnosis of PML (Okada et al, 2002, supra). A tissue biopsy, is an invasive technique and is associated with pain as well as risk of infection, hemorrhage, damage to healthy tissue, and related complications.
What is needed is a simple and easy method for detection of polyomavirus reactivation and active infection in patients at risk, for instance, of developing polyomavirus-induced diseases, including but not limited to, PML.